Monoclonal antibodies (mAb) have become important protein-based therapeutics for treating various human diseases such as cancer, infectious diseases, inflammation, and autoimmune diseases. Currently, more than 20 monoclonal antibody products have been approved by the Food and Drug Administration, and approximately 20% of all biopharmaceuticals currently being evaluated in clinical trials are monoclonal antibodies (Daugherty et al., Adv. Drug Deliv. Rev. 58:686-706, 2006).
Antibodies can be administered for example via parenteral route, such as by intravenous (IV), subcutaneous (SC) or intramuscular (IM) injection. The SC or IM route reduces the treatment cost and improves convenience for patients and healthcare providers during administration. To be effective and pharmaceutically acceptable, parenteral formulations should preferably be sterile, stable, syringeable, injectable, and nonirritating. These characteristics result in manufacturing, storage, and usage requirements that make injectable formulations difficult dosage forms to develop, in particular formulations having high protein concentrations.
As with any protein therapeutic, antibodies are subject to physical and chemical instability such as aggregation, denaturation, crosslinking, deamidation, isomerization, oxidation and clipping (Wang et al., J. Pharm. Sci. 96:1-26, 2007). Thus, formulation development to identify factors critical for antibody stability is paramount in the development of commercially viable antibody pharmaceuticals.
The required small volumes (typically 0.5-2 mL) for SC or IM injections pose additional formulation challenges as the dosing requires high concentration antibody formulations typically between 100 mg-1 g of protein per dose to achieve therapeutic levels in a patient. The highly concentrated protein formulations often result in increased protein aggregation, poor stability and increased viscosity, impairing injectability and having negative ramifications during process, manufacture, and storage (Shire et al., J. Pharm. Sci. 93:1390-1402, 2004).
Current commercial monoclonal antibody products administered by SC or IM route are usually formulated in aqueous buffers such as phosphate or L-histidine buffer, with excipients or surfactants such as mannitol, sucrose or polysorbate 80 to prevent aggregation and improve stability. Reported antibody concentrations are up to 100 mg/mL in aqueous formulations (Wang et al., J. Pharm. Sci. 96:1-26, 2007). Viscosity of the aqueous formulations has been reduced by addition of salts (U.S. Pat. No. 7,666,413) or organic or inorganic acids (U.S. Pat. No. 7,740,842).
Non-aqueous antibody or protein formulations have been described. WO2006/071693 describes a non-aqueous suspension of up to 100 mg/mL monoclonal antibody in a formulation having a viscosity enhancer (polyvinylpyrrolidone, PVP) and a solvent (benzyl benzoate (BB) or PEG400). WO2004/089335 describes about 100 mg/mL non-aqueous lysozyme suspension formulations containing PVP, glycofurol (GF), BB, benzyl alcohol (BA), or PEG400. US2008/0226689A1 describes a 100 mg/mL human growth hormone (hGH) single phase, three vehicle component (polymer, surfactant and a solvent) non-aqueous viscous formulations. U.S. Pat. No. 6,730,328 describes non-aqueous, hydrophobic, non-polar vehicles of low reactivity (such as perfluorodecalin) for protein formulations. These formulations are non-optimal having, for example, high viscosity that impairs processing, manufacturing and injection, the presence of multiple vehicle components in the formulations, and potential regulatory challenges associated with using not yet approved polymers.
Thus, there is a need to develop improved high concentration non-aqueous formulations.